Mitochondrial dynamics, manifest as ability of mitochondria to change morphology and motility, play a vital role in neuronal response to fluctuating energy demands. Impairment of mitochondrial dynamics contributes to different disorders such as Alzheimer?s, Parkinson?s, and Huntington?s diseases (HD). In HD, interaction of mutant huntingtin (mHtt) with dynamin related protein 1 (Drp1) results in an increased Drp1 activity, leading to augmented mitochondrial fission, accompanied by reduced mitochondrial traffic. Despite significant effort, the molecular mechanisms, leading to mHtt-induced changes in mitochondrial morphology and motility are not completely understood. In preliminary experiments, we found that CRMP2, a protein implicated in axon guidance and regulation of neurite outgrowth, regulates mitochondrial dynamics. A mechanistic link between CRMP2 and regulation of mitochondrial dynamics has never been investigated. CRMP2 binds to neuronal mitochondria and in its dephosphorylated form to mHtt. CRMP2 physically interacts with Drp1, Mitofusin 2, and Miro 2, proteins involved in regulation of mitochondrial fission, fusion, and motility, respectively. Downregulation of CRMP2 with siRNA leads to increased fission and reduced mitochondrial traffic, implicating CRMP2 in regulation of mitochondrial dynamics. CRMP2 hyperphosphorylation after inhibition of protein phosphatases 1 and 2A correlates with augmented fission and reduced mitochondrial traffic. Conversely, decreasing CRMP2 phosphorylation can prevent these alterations. Finally, we found CRMP2 downregulation and hyperphosphorylation in striatal tissues from YAC128 HD mouse model and in postmortem striatal tissues of HD patients. Overall, the literature and our preliminary data strongly suggest that CRMP2 is involved in regulation of mitochondrial morphology and motility and CRMP2 hyperphosphorylation contributes to HD pathogenesis leading to excessive fission, reduced mitochondrial traffic, and neuronal loss. Dephosphorylated CRMP2 binds to mHtt and to proteins involved in mitochondrial dynamics and reduces their activities, whereas CRMP2 downregulation and hyperphosphorylation disrupts these protein-protein interactions, liberates binding partners of CRMP2, and increases their activities. In Aim 1, we will determine CRMP2 localization in mitochondria, establish protein interaction partners, and assess the extent to which CRMP2 regulates mitochondrial dynamics in neurons. In Aim 2, the mechanisms of CRMP2-medited regulation of mitochondrial dynamics will be determined. In Aim 3, we will establish CRMP2-mediated mechanisms contributing to defects of mitochondrial dynamics and cell death in human neurons expressing mHtt. Finally, in Aim 4, we will assess to what extent CRMP2 dephosphorylation alters protein-protein interactions, protects neurons, and corrects behavioral deficits in animal models of HD. The proposed study will considerably improve our understanding of HD pathophysiology, lay a solid foundation for identifying new mechanisms of HD pathogenesis, and open novel avenues in HD research.